Is Primodos ‘the forgotten thalidomide’?

Author

Disclosure statement

Neil Vargesson receives or has received funding for his research from the Royal Society, Wellcome Trust, Imperial College London, University of Aberdeen. I have been contacted by and spoken with alleged Primodos affected people and discussed the scientific evidence for and against its actions.

Primodos, an oral hormonal pregnancy test, was introduced to the UK in the late 1950s. A decade later, claims were made by some researchers that Primodos was linked to birth defects.

Isabel Gal, a paediatrician at Queen Mary’s Hospital for Children in Surrey, England, was the first to publish a paper (1967) suggesting a link between Primodos and birth defects. Several other studies subsequently suggested links between hormonal pregnancy tests (HPTs) and birth defects including to the limbs, face, neural tube and heart. Other studies found no association.

Primodos continued to be used in the UK until 1978. The drug was voluntarily withdrawn from the market, for commercial reasons, following the arrival of urine-based pregnancy tests.

Schering, the German company which made Primodos, and Bayer, which now owns Schering, continues to deny any link between deformities in children and the drug.

How Primodos works

Primodos consists of two active ingredients: norethisterone, an artificial progesterone, and ethinyl estradiol, an artificial oestrogen.

If a woman wanted to find out if she was pregnant, she would take the Primodos pills. If she menstruated, it indicated that she wasn’t pregnant. And if she didn’t menstruate, it confirmed that she was pregnant.

Although Primodos is no longer available, the drug’s main ingredient, norethisterone, is still used – but at much lower doses – to treat a range of health problems, including abnormal bleeding from the uterus, endometriosis, and amenorrhoea (absence of menstruation). It can also be used as an emergency contraceptive (the “morning-after pill”) in combination with other hormones.

Inconclusive results

Not all studies have found statistically significant associations between Primodos and birth defects. A recent study of patient data found an association between the use of HPTs and neural tube problems, and a very strong association with a rare bladder abnormality. But the authors point out that this type of rare defect is not seen in children born to mothers who used other types of hormone drugs, including oral contraceptive pills that contain progesterone, during pregnancy.

These types of studies use data collected a few decades ago, when the methods for collecting data weren’t perhaps as stringent as they are today. They also rely on the memory of mothers as to when in their pregnancy they took the drug.

Another problem is that the HPT test simply determined whether a woman was pregnant or not. It couldn’t determine how long she had been pregnant for, so knowing the precise time of exposure is difficult.

Also, the somewhat limited experimental evidence from animal studies exposed to Primodos or exposed to its active components are also inconclusive. Some data shows negative effects (including death) and other studies indicate little or no direct effect on embryo development.

Making the case

The point in pregnancy when HPTs were used varied depending on when the woman became aware that she might be pregnant. If we assume four to seven weeks after conception, then this is a period of incredibly rapid growth and organ formation in the embryo. Anything altering this process could result in birth defects.

The severity and type of defect could be related to the timing of exposure through disrupting organ formation, as demonstrated for thalidomide. However, there’s an approximate 3% rate of naturally occurring birth defects in the world. So it’s possible that the damage in the people exposed to Primodos could be due to other factors.

Since Primodos was taken off the market not much published research has been carried out on animals to understand what the drug may or may not do to the embryo. And many of the studies that were carried out were conducted decades ago when analytical methods and tools were not as advanced as they are today.

Today, norethisterone is used to control a variety of hormonal conditions, but it is not recommended for use in pregnancy. There is also speculation that it may have been used to induce abortions. All of these things taken together mean questions about the safety of Primodos persist.

At last, a formal inquiry

Today, the debate about whether or not Primodos was responsible for birth defects still rages. And the demands for an apology and compensation are getting louder.

Hopefully, answers will soon be forthcoming. Early in 2015, the UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) issued a call for evidence for any information considered relevant to a possible association between the use of oral HPTs and adverse effects on the pregnancy or subsequent birth defects in the child. The evidence will be reviewed by a group of independent experts. An MHRA appointed inquiry panel will report its findings this year. It will hopefully determine, once and for all, whether Primodos deserves to be called “the forgotten thalidomide”.